N-derivatives of (phenylethyl-β-ol) amine, a process for their preparation and pharamaceutical compositions containing the same

ABSTRACT

The invention relates to a N-(2,4- or 2,5-disubstituted tetrahydrofuryl alkyl)-N-(phenylethyl-β-ol)amine derivative, under a racemic or enantiomer form, of general formula I ##STR1## wherein R represent various radicals and n is of from 1 to 10, to a process for the preparation of said derivative, and to pharmaceutical compositions comprising the same.

The invention relates to N-derivatives of (phenylethyl-β-ol)amine, theirprocesses of preparation, and pharmaceutical compositions based thereon.These products are agonists of β-adrenergic receptors.

The invention provides a N-(2,4- or 2,5-disubstituted tetrahydrofurylalkyl)-N-(phenylethyl-β-ol)amine derivative, under a racemic orenantiomer form, of general formula I ##STR2## wherein R represents astraight or branched alkyl group comprising from 1 to 10 carbon atoms;an heteroaryl group, a phenyl radical or a substituted phenyl radical ofthe formula ##STR3## in which the radicals R₁, R₂, R₃, R₄ and R₅independently represent a hydrogen atom, a halogen atom, an alkoxyradical comprising from 1 to 5 carbon atoms, or an alkylsulphonylradical comprising from 1 to 5 carbon atoms;

n is from 1 to 10;

and pharmaceutically acceptable salts thereof. Such salts are formedfrom organic or mineral acids, such as hydrochloric, hydrobromic,sulphuric, fumaric or maleic acid.

The state of the art may be illustrated by British patent applicationNo. 2 230 775, British patent application No. 2 140 800 and Europeanpatent application No. 422 889: said patent applications refer toether-like compounds, with an ether bond instead of the --(CH₂)_(n) --chain of the compounds of the invention.

The invention also provides a process for the preparation of a compoundof formula I, the said process comprising the following steps:

condensation of a substituted benzylamine of general formula II ##STR4##with methyl 5-bromoacetyl salicylate III, in a protic solvent oracetonitrile, in presence of triethylamine, at a temperature of fromroom temperature to the boiling point of the reaction mixture, for 2 to18 hours,

then reduction, under inert atmosphere, with an hydride as reducingagent, in an ethereal solvent, for 2 to 8 hours, at a temperature offrom 0° C. to room temperature, of compound IV so obtained of theformula ##STR5## and finally, debenzylation of compound V of the formula##STR6## by hydrogenation in presence of an appropriate catalyst, at 2to 5.5 bar, at a temperature of from room temperature to 40° C. for 10minutes to 5 hours.

According to the invention, the condensation reaction may be performedin a protic solvent such as, for instance, dimethyl sulfoxide. In thereduction reaction, the reducing agent used may be preferably hydridessuch as, for instance, LiAlH₄ ; the reaction may be carried out in anethereal solvent such as, for instance, tetrahydrofuran or diethylether. In the debenzylation reaction, the appropriate catalyst may beselected of from Pd/C or PtO₂. In a preferred embodiment, when R standsfor a heteroaryl group or a phenyl radical substituted by one or morehalogen atoms, the debenzylation may be performed with PtO₂ as catalyst,at room temperature, for 10 to 30 minutes and at 4-5.5 bar. In an otherpreferred embodiment, when R stands for an alkyl group or a phenylradical optionally substituted by one or more alkoxy or alkylsulphonylradicals, the debenzylation may be performed with Pd/C (10%) at 2-3.5bar.

These and other aspects of the present invention may be more fullyunderstood by reference to the following drawings wherein:

FIG. 1, labelled "Reaction Scheme 1", illustrates a preparation processfor making a compound of formula I;

FIG. 2, labelled "Reaction Scheme 2", illustrates a preparation processfor making a compound of formula II;

FIG. 3, labelled "Reaction Scheme 3", illustrates another preparationprocess for making a compound of formula II;

FIG. 4, labelled "Reaction Scheme 4", illustrates another preparationprocess for making a compound of formula II;

FIG. 5, labelled "Reaction Scheme 5", illustrates another preparationprocess for making a compound of formula II; and

FIG. 6, labelled "Reaction Scheme 6", illustrates another preparationprocess for making a compound of formula II.

The above preparation process may be illustrated by the reactionscheme 1. The cis and trans isomers of compounds of formula I can beobtained either by preparative HPLC of the racemic compounds, orstarting from cis/trans isomers of intermediate compounds. Thesecompounds can be separated at different stages of the synthesis,particularly when R stands for an aryl radical. Each of cis and transcompounds is a mixture of two enantiomers which may be obtained byasymmetric synthesis.

The bromocetone III can be obtained by a Fries rearrangement of thephenolic ester of methyl salicylate, followed by bromination of themethyl cetone.

The starting compounds II are new compounds and may be obtained byvarious ways according to the positions of the substituents and thenumber of carbon atoms n in the alkyl chain. Benzylamine can becondensed with a cyclopentyl heterocycle substituted with a haloalkyl,or a corresponding mesylate of the alcohol.

The various processes for the preparation of the starting compound IImay be illustrated in the enclosed reaction schemes 2 to 6: the reactionschemes 2, 3, 4 and 5 illustrate the synthesis of the starting compoundII with a 2,5-disubstitution wherein R stands for an optionallysubstituted phenyl group and n=1, 2, 3 and n>3 respectively; moreover,the reaction scheme 6 describes the synthesis of the starting compoundII with a 2,4-disubstitution wherein R stands for an optionallysubstituted phenyl group and wherein n=1. Obviously, when R stands foran heteroaryl or an alkyl group, the reaction schemes may be asdescribed in the above reaction schemes 2 to 6.

Finally, the invention provides a pharmaceutical composition comprisingof (phenylethyl-β-ol)amine derivative of the formula I as defined aboveor a pharmaceutically acceptable salt of such a derivative, in admixturewith a pharmaceutically acceptable diluent or carrier.

In the description of the preparation process of any starting compoundsII as illustrated below and more specifically when R stands for asubstituted phenyl radical, a letter is added, as a superscript, to thenumber of the compound to simplify and distinguish the differentsubstituents for a given value of n. This convention, followedthroughout, is as follows:

    ______________________________________                                        Substitution                                                                          R.sub.1 R.sub.2 R.sub.3                                                                             R.sub.4                                                                              R.sub.5                                                                           n   Indice                           ______________________________________                                        2,5-    H       H       H     H      H   1   a                                2,5-    H       CH.sub.3 O                                                                            CH.sub.3 O                                                                          CH.sub.2 O                                                                           H   1   b                                2,5-    CH.sub.3 O                                                                            CH.sub.3 O                                                                            CH.sub.3 O                                                                          H      H   1   c                                2,5-    Cl      H       H     H      H   1   d                                2,5-    H       Cl      H     H      H   1   e                                2,5-    F       H       H     H      H   1   f                                2,5-    H       CH.sub.3 O                                                                            C.sub.3 H.sub.7 O                                                                   CH.sub.3 SO.sub.2                                                                    H   1   g                                2,5-    H       H       H     H      H   2   h                                2,5-    H       CH.sub.3 O                                                                            CH.sub.3 O                                                                          CH.sub.3 O                                                                           H   2   i                                2,5-    H       CH.sub.3 O                                                                            CH.sub.3 O                                                                          CH.sub.3 O                                                                           H   3   j                                2,5-    Cl      H       H     H      H   3   k                                2,5-    H       CH.sub.3 O                                                                            CH.sub.3 O                                                                          CH.sub.3 O                                                                           H   7   l                                2,4-    H       CH.sub.3 O                                                                            CH.sub.3 O                                                                          CH.sub.3 O                                                                           H   1   m                                2,4-    Cl      H       H     H      H   1   n                                ______________________________________                                    

A) Process for the preparation of starting compound II disubstituted inthe 2,5-position with n=1

A-1) Process according to reaction scheme 2, for the preparation ofcompound II wherein R=aryl

5-aryl-5-hydroxy-pentene--group compounds 1

The aldehydes used are in general commercial. For the preparation ofcompound 1 g, the aldehyde was obtained starting from iodovanilinaccording to the method of A. S. Thomson (Tetrahedrom Letters, vol. 31,p. 6953, 1990).

The reaction was carried out under argon. To the Grignard reagentobtained from 11 g (80 mmol) of 4-bromobutene and 2 g (80 mmol) ofmagnesium in tetrahydrofuran (THF), 50 mmol of the appropriate aldehydein 100 ml of THF was added at room temperature. The stirring wasmaintained for 1 hour. The reaction mixture was quenched with a 10%aqueous solution of ammonium chloride and extracted with chloroform.After the usual workup, the residue was purified by flash chromatography(light petroleum/ethyl acetate 80:20 then 70:30) to give the alcohol 1as a viscous product.

Compound 1_(a) : R_(f) =0.37 (PE/AcOEt 80:20)

Compound 1_(b) : R_(f) =0.43 (PE/AcOEt 50:50)

Compound 1_(c) : R_(f) =0.39 (PE/AcOEt 50:50)

Compound 1_(d) : R_(f) =0.55 (PE/AcOEt 95:5)

Compound 1_(e) : R_(f) =0.35 (PE/AcOEt 90:10)

Compound 1_(f) : R_(f) =0.23 (PE/AcOEt 90:10)

Compound 1_(g) : R_(f) =0.27 (PE/AcOEt 70:30)

The alcohols all show in ¹ H-NMR (100 MHz, CDCl₃, TMS, δ), the followingsignals: 5.8 (m, 1H, CH═C); 5.0 (t, 2H, C═CH₂); 4.6 (t, 1H, CHOH); 2.1(2m, 4H, CH₂ --CH₂).

2-aryl-5-iodomethyl-tetrahydrofuran--group compounds 2

A stirred solution of alcohol 1 (71 mmol) in 250 ml of ether and 70 mlof water was cooled to 0° C. 8.9 g (1.5 equivalents) of sodiumbicarbornate (NaHCO₃), then iodine (27 g, 1.5 equivalents), were addedby small portionwise. The mixture was allowed to warm to roomtemperature and stirred overnight. A solution of sodium thiosulphate(10%) was added. After decantation and washing, the organic phase wasdried and concentrated. The thus obtained residue was purified by flashchromatography (light petroleum/ethyl acetate 80:20 then 30:70) to yieldthe compound 2 as a mixture (yield about 80-85%). In some cases, the cisand trans isomers may be isolated.

Compound 2_(a) : R_(f) (cis)=0.25 R_(f) (trans)=0.31 (PE/AcOEt 95:5)

Compound 2_(b) : R_(f) (cis)=0.29 R_(f) (trans)=0.35 (PE/AcOEt 70:30)

Compound 2_(c) : R_(f) (rac)=0.39 (PE/AcOEt 80:20)

Compound 2_(d) : R_(f) (rac)=0.70 (PE/AcOEt 95:5)

Compound 2_(e) : R_(f) (cis)=0.36 R_(f) (trans)=0.45 (PE/AcOEt 90:10)

Compound 2_(f) : R_(f) (rac)=0.48 (PE/AcOEt 95:5)

IR (cm⁻¹): ν_(C-O-C) =1600; ν_(OCH3) =1120 ¹ H-NMR (100 MHz, CDCl₃ TMS,δ), characteristic signals: Trans compound: 5.0 (m, 1H, H₂); 4.3 (m, 1H,H₅); 3.3 (m, 2H CH₂ I); 2.5-1.7 (m, 4H, CH₂ --CH₂) Cis compound: 4.9 (m,1H, H₂); 4.1 (m, 1H, H₅).

When the phenyl radical is substituted by one or more alkylsulphonylgroups, the synthesis of compound II may be performed through theintermediates 3 and 4 as shown in reaction scheme 2.

2-(3'-methoxy-4'-propyloxy-5'-methylsulphonyl-phenyl)-5-hydroxymethyltetrahydrofuran 3

A solution of anhydrous m-chloroperbenzoic acid (m-CPBA) (14.7 g, 85.2mmol) in 100 ml of dry dichloromethane was added slowly at 0° C. to asolution of 6.3 g (21.3 mmol) of alcohol 1 g in 200 ml of anhydrousdichloromethane. Stirring was maintained at room temperature overnight,then a saturated solution of sodium thiosulphate was added. Afterdecantation, the organic phase was washed with 1N sodium hydroxidesolution, then with water, and dried. After elimination of the solvent,the residue thus obtained was purified on a silica gel column (eluentCH₂ Cl₂ /MeOH 98:2) to give a viscous product (5.12 g, yield 70%).

TLC: R_(f) =0.43 (CHCl₃ /MeOH 95:5) IR (cm⁻¹): ν_(OH) =3500; ν_(CH3SO2)=1310 ¹ H NMR (100 MHz, CDCl₃, TMS, δ), characteristic signals: 5 (m,1H, H₂); 4.3 (m, 1H, H₅); 3.8 (m, 2H, CH₂ OH); 3.2 (s, 3H, CH₃ SO₂).

Mesylate of2-(3'-methoxy-4'-propyloxy-5'-methylsulphonyl-phenyl)-5-hydroxymethyltetrahydrofuran 4

The mesylate 4 was obtained by action of mesyl chloride (MeSO₂ Cl) onthe compound 3, and used without purification in the following step.

TLC: R_(f) =0.54 (CHCl₃ /MeOH 95:5) ¹ H NMR (100 MHz, CDCl₃, TMS, δ):4.3 (m, 3H, H₅ and CH₂ OMes).

2-aryl-5-benzylaminomethyl-tetrahydrofuran--group compounds II

A solution of benzylamine (4 equivalents) and either the iodide 2 (42mmol) or the mesylate 4 in 200 ml of anhydrous acetonitrile was refluxedfor 5 hours, then evaporated to dryness and taken up in 250 ml ofchloroform. After washing with water and drying, the solvent waseliminated. The thus obtained residue was purified by flashchromatography (eluent CHCl₃ then CHCl₃ /MeOH 95:5). The amine wasobtained in a yield about 70-75%.

Compound II_(a) : R_(f) (cis)=0.16 R_(f) (trans)=0.22 (AcOEt)

Compound II_(b) : R_(f) (cis)=0.15 R_(f) (trans)=0.24 (CHCl₃ /MeOH 95:5)

Compound II_(c) : R_(f) (rac)=0.28 (CHCl₃ /MeOH 95:5)

Compound II_(d) : R_(f) (rac)=0.42 (CHCl₃ /MeOH 90:10)

Compound II_(e) : R_(f) (cis)=0.26 R_(f) (trans)=0.25 (CHCl₃ /MeOH 96:4)

Compound II_(f) : R_(f) (rac)=0.25 (AcOEt)

Compound II_(g) : R_(f) (rac)=0.25 (CHCl₃ /MeOH 95:5)

IR (cm⁻¹): ν_(NH) =3300 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ),characteristics signals: Trans compound: 4.9 (t, 1H, H₂); 4.3 (m, 1H,H₅); 3.8 (d, 2H, NCH₂ O); 2.7 (d, 2H, CH₂ N). Cis compound: 4.1 (m, 1H,H₅); 2.8 (d, 2H, CH₂ N).

The enantiomers of compound II(cis) and compound II(trans) may beobtained separately from the corresponding enantiomers 2(cis) and2(trans) respectively, or 3(cis) and 3(trans) respectively, according tothe process as described above (cf. A-1) Preparation of compound II).

Said enantiomers of compound 2 or 3 may be obtained by oxydation of thecorresponding alcohol 1 followed by a symmetric reduction andcyclisation. The synthesis of such enantiomers is hereunder illustratedfor the compound II_(b) according to the following successive steps 1'and 2'.

Step 1': 4-(3',4',5'-trimethoxybenzoyl)-butene

A solution of alcohol 1_(b) (4 mmol) in CH₂ Cl₂ (3 ml) was addeddropwise to a mixture of pyridinium chlorochromate (1.5 eq.), sodiumacetate (0.04 eq.) and celite (1.5 g) in anhydrous CH₂ Cl₂ (8 ml) at 0°C. under nitrogen atmosphere. The reaction mixture was allowed to roomtemperature and stirred for about 4 hours (followed by TLC). Theinsoluble materials were eliminated by filtration. The filtrate wasevaporated and the thus obtained residue was purified by flashchromatography (PE/AcOEt 70:30), to give the ketone as a white solid(yield 81%).

Melting point: mp=64° C.; TLC: R_(f) =0.60 (PE/AcOEt 1:1) IR (cm⁻¹)ν_(CO) =1680; ν_(O) =1590 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ): 7.3 (s, 2H,O); 5.9 (m, 1H, HC═C); 5.1 (m, 2H, ═CH₂); 3.9 (s, 9H, OCH₃); 3.1 (m, 2H,--C(O)--CH₂); 2.5 (q, 2H, CH₂ --C═)

Step 2': 5-(3'4'5'-trimethoxyphenyl)-5-(-)-hydroxypentene

This step was performed according to Brown H. C., J. Org. Chem. 50, 5446(1985).

A solution of (-) DIP chloride (β-chlorodiisopinocamphocyl borane) (1.4eq.) in anhydrous THF (4.5 ml) was added dropwise to a solution ofketone (31.8 mM) in dry THF (45 ml) at 0° C. under stirring. The mixturewas allowed to warm to room temperature and stirred overnight. Thesolvent was evaporated and the thus obtained residue was taken up indiethyl ether and diethylethanolamine (2.2 eq.) was added. After 30minutes, the insoluble material was filtered off and washed withpentane. Elimination of the filtrate gave a viscous product which waspurified by flash chromatography (PE/AcOEt 3:1) to afford the (-)alcohol (yield 65%).

TLC: R_(f) =0.34 (PE/AcOEt 2:1) [α]_(D) ²³ =-32.6 (CHCl₃, 0.82 g/100 ml)The (+) alcohol may be obtained according to the process as describedabove but by using (+) DIPCl instead of (-)-DIPCl.

[α]_(D) ²³ =+30.49 (CHCl₃, 0.9 g/100 ml)

The compounds 2_(b) (+) trans and 2_(b) (-) trans may be obtainedaccording to the process as described above (A-1) Preparation ofcompound 2), starting from the appropriate alcohols 1_(b) (+) trans and1_(b) (-) trans respectively.

Compound 2_(b) (+) trans: [α]_(D) ²³ =+47.05 (CHCl₃, 1.27 g/100 ml)

Compound 2_(b) (-) trans: [α]_(D) ²³ =-46 (CHCl₃, 1.8 g/100 ml)

The compounds II_(b) (+) trans and II_(b) (-) trans may be obtainedaccording to the process as described above (cf. A-1: Preparation ofcompound II), starting from the appropriate compounds 2_(b) (+) transand 2_(b) (-) trans respectively.

Compound II_(b) (+) trans: [α]_(D) ²³ =+34.545 (CHCl₃, 2.2 g/100 ml)

Compound II_(b) (-) trans: [α]_(D) ²³ =-35.1 (CHCl₃, 2 g/100 ml)

A-2) Process for the preparation of compound II wherein R=heteroaryl

2-(4'-pyridyl)-5-hydroxy-pentene 1

This compound 1 was obtained as described above and purified by flashchromatography (eluent: AcOEt) to yield a brown oil (60%)

TLC: R_(f) =0.19 (AcOEt) IR (cm⁻¹): ν_(pyridine) =1620 and 1590. ¹ H-NMR(100 MHz, CDCl₃, TMS, δ): 8.5 (m, 2H, H.sub.α N); 7.3 (m, 2H, Haromatic); 5.8 (m, 1H, HC═); 5 (m, 2H, C═CH₂); 4.7 (t, 1H, CHOH);1.9-2.2 (m, 5H, OH and 2CH₂).

2-(4'-pyridyl)-5-iodomethyl-tetrahydrofuran 2

This compound was obtained from the corresponding alcohol 1, asdescribed above, and purified by flash chromatography (eluent PE/AcOEt30:70 then 20:80) (70%).

TLC: R_(f) =0.22 (PE/AcOEt 30:70) IR (cm⁻¹): ν_(pyridine) =1600 and1560; ν_(C-O-C) =1050 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ): 8.5 (m, 2H,H.sub.α N); 7.3 (m, 2H, 2H aromatic); 5 (m, 1H, H₂); 4.3 (m, 1H, H₅);3.4 (m, 2H, CH₂ I); 2.5-1.7 (m, 4H, CH₂ --CH₂).

2-(4'-pyridyl)-5-benzylaminomethyl-tetrahydrofuran II

This amine was obtained from the corresponding compound 2, as describedabove, and purified by flash chromatography (eluent CHCl₃ /MeOH 90:10then 80:20 and 70:30).

TLC: R_(f) =0.40 (CHCl₃ /MeOH 70:30).

A-3) Process for the preparation of compound II wherein R=alkyl

The successive steps for the preparation of the compounds 1, 2 and IIrespectively, are performed in the same conditions as described above(cf. A-1).

B) Process for the preparation of the starting compound II disubstitutedin the 2,5-positions with n=2

B-1) Process according to reaction scheme 3, for the preparation ofcompound II wherein R=aryl

2-aryl-5-cyanomethyl-tetrahydrofuran--group Compounds 5

A mixture of 2-aryl-5-iodomethyl tetrahydrofuran 2 and potassium cyanide(1.5 equivalents) in 50 ml of dimethylsulphoxide was heated at 80° C.for 3 hours. After cooling, 30 ml of brine was added and the product wasextracted with ether. The elimination of the solvent leaves a residuewhich crystallized or which was purified by chromatography on a silicagel column (eluent PE/AcOEt 50:50 then 40:60). The compounds 5 wereobtained in a yield of the order of 70-75%.

Compound 5_(h) : R_(f) (cis)=0.32 R_(f) (trans)=0.38 (PE/AcOEt 70:30)

Compound 5_(i) : R_(f) (cis)=0.34 R_(f) (trans)=0.41 (PE/AcOEt 40:60)

Compound 5_(h) cis and 5_(i) cis are viscous compounds. Compound 5_(i)trans: m_(p) : 98°-100° C.

IR (cm⁻¹): ν_(C).tbd.N =2240 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ),characteristics signals: Trans compound: 5.1 (m, 1H, H₂); 4.5 (m, 1H,H₅); 2.7 (m, 2H, CH₂ CN). Cis compound: 4.9 (m, 1H, H₂); 4.3 (m, 1H,H₅).

2-aryl-5-(β-amino-ethyl)-tetrahydrofuran--group compounds 6

The reduction of the nitrile 5 was effected with LiAlH₄ (3 equivalents)in THF at room temperature. After hydrolysis in basic conditions, theproduct was extracted with chloroform, dried and the solvent waseliminated. The viscous oil 6 thus obtained was used withoutpurification. Crude yield 80%.

Compound 6_(h) : R_(f) (cis)=0.28 R_(f) (trans)=0.35 (CHCl₃ /MeOH/NH₃80:19:1)

Compound 6_(i) : R_(f) (cis)=0.25 R_(f) (trans)=0.31 (CHCl₃ /MeOH/NH₃80:19:1)

IR (cm⁻¹) ν_(NH2) =3350-3300 ¹ H NMR (100 MHz, CDCl₃, TMS, δ), principalsignals: Trans compound: 4.8 (m, 1H, H₂); 4.3 (m, 1H, H₅); 2.9 (m, 2H,CH₂ N). Cis compound: 4.7 (m, 1H, H₂); 4.2 (m, 1H, H₅).

2-aryl-5-(β-benzoylamino-ethyl)-tetrahydrofuran--group compounds 7

A solution of benzoyl chloride (1 equivalent) in dichloromethane wasadded slowly at 0° C. to a mixture of the amine 6 and triethylamine (1.1equivalents) in dichloromethane. Stirring was maintained for 1 hour.After filtration, the solvent was eliminated and the product waspurified on a silica gel column (eluent CHCl₃ /MeOH 98:2 then 97:3)(yield 90%).

Compound 7_(h) : R_(f) (cis)=0.52 R_(f) (trans)=0.60 (CHCl₃ /MeOH 97:3)

Compound 7_(i) : R_(f) (cis)=0.50 R_(f) (trans)=0.57 (CHCl₃ /MeOH 97:3)

IR (cm⁻¹): ν_(NH) =3300; ν_(CO) =1710 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ),principal signals: Trans compound: 7.7 (m, 2H, H α to CO); 4.9 (m, 1H,H₂); 4.4 (m, 1H, H₅); 3.4 (m, 2H, CH₂ NCO). Cis compound: 4.8 (m, 1H,H₂); 4.2 (m, 1H, H₅).

2-aryl-5-(β-benzylamino-ethyl)-tetrahydrofuran--group compounds II

Compounds II were obtained by reduction of the amide 7 with LiAlH₄ underreflux in THF. The product was purified by chromatography on a silicagel column (eluent CHCl₃ then CHCl₃ /MeOH 95:5) (yield about 70%).

Compound II_(h) : R_(f) (cis)=0.28 R_(f) (trans)=0.30 (CHCl₃ /MeOH90:10)

Compound II_(i) : R_(f) (cis)=0.24 R_(f) (trans)=0.29 (CHCl₃ /MeOH90:10)

IR (cm⁻¹): ν_(NH) =3300 ¹ H NMR (100 MHz, CDCl₃, TMS, δ), principalsignals: Trans compound: 4.9 (m, 1H, H₂); 4.3 (m, 1H, H₅); 3.7 (s, 2H,NCH₂ O); 2.8 (m, 2H, CH₂ N) Cis compound: 4.8 (m, 1H, H₂); 4.1 (m, 1H,H₅).

B-2) Process for the preparation of compound II wherein R=alkyl orheteroaryl

The successive steps for the preparation of compounds 5, 6, 7 and IIrespectively, may be performed as described above (cf. B-1).

C) Process for the preparation of the starting compound II disubstitutedin the 2,5-positions with n=3

C-1) Process according to reaction scheme 4, for the preparation ofcompound II wherein R=aryl

2-aryl-5-(β-dicarboxyethyl-ethyl)-tetrahydrofuran--group compounds 8

To a suspension of sodium hydride (1.1 equivalents) in 50 ml ofanhydrous THF, a solution of ethyl malonate (1 equivalent) was addeddropwise. Stirring was maintained for 1 hour at room temperature.2-aryl-5-iodomethyl-tetrahydrofuran 2 (1 equivalent) dissolved in THFwas then added at 0° C., and the mixture was heated under reflux for 30hours. After cooling, the sodium iodide was filtered off. The solventwas evaporated off and the residue was dissolved in ether and washed.After the usual workup, the residue was purified by flash chromatography(eluent PE/AcOEt 90:10 then 80:20) to afford a colourless viscous oil ina yield about 60%.

Compound 8_(j) : R_(f) (cis)=0.28 R_(f) (trans)=0.31 (PE/AcOEt 70:30)

Compound 8_(k) : R_(f) (rac)=0.51 (PE/AcOEt 70:30)

IR(cm⁻¹): ν_(CO) =1740 and 1730. ¹ H-NMR (100 MHz, CDCl₃, TMS, δ)principal signals: Trans compound: 4.9 (t, 1H, H₂); 4.2 (m, 5H, H₅ and 2OCH₂ CH₃); 3.65 [t, 1H, CH(CO₂ Et)₂ ]; 1.2 (m, 6H, 2 CH₃) Cis compound:4.8 (t, 1H, H₂).

2-aryl-5-(β-carboxy-ethyl)-tetrahydrofuran--group compounds 9

An ethanolic solution of potassium hydroxide (2.05 equivalents) wasadded slowly to a solution of the diester 8 in ethanol. After 1.5 hours(monosaponification, monitored by TLC), the mixture was refluxedovernight, evaporated to dryness, and taken up in water. The aqueousphase was first extracted with chloroform, then acidified and extractedagain with chloroform. The elimination of the solvent gave the diacid(yield 98%). Decarboxylation was obtained by warming the diacid on anoil-bath at 120° C. until the evolution of carbon dioxide ceased (about1 hour). After cooling, the acid 9 was obtained in a quantitative yield.

IR (cm⁻¹): ν_(OH) chelate =3400-3300; ν_(CO) =1730 ¹ H-NMR (100 MHz,CDCl₃, TMS, δ), principal signals: Trans compound: 5.7 (1H, OH); 4.9 (t,1H, H₂); 4.2 (q, 1H, H₅); 2.6 (m, 2H, CH₂ CO) Cis compound: 7.3 (1H,OH); 4.8 (t, 1H, H₂); 4.1 (m, 1H, H₅).

2-aryl-5-(γhydroxy)-propyl-tetrahydrofuran--group compounds 10

The reduction of the acid 9 by LiAlH₄ (2.5 equivalents), at roomtemperature, lead to the alcohol 10. The purification was performed on asilica gel column (eluent AcOEt/PE 90:10 then pure AcOEt). Yield: 79%.

Compound 10_(j) : R_(f) (cis)=0.28 R_(f) (trans)=0.32 (AcOEt/PE 90:10)

Compound 10_(k) : R_(f) (rac)=0.40 (AcOEt)

IR (cm⁻¹): ν_(OH) =3400 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principalsignals: Trans compound: 4.9 (t, 1H, H₂); 4.2 (m, 1H, H₅); 4.1 (m, 2H,CH₂ OH); 2.8 (1H, OH). Cis compound: 4.8 (t, 1H, H₂); 4.1 (m, 3H, H₅ andCH₂ OH); 2.6 (1H, OH).

Mesylate of 2-aryl-5-(γ-hydroxy)-propyl)-tetrahydrofuran--groupcompounds 11

The mesylate was obtained by action of mesyl chloride in dichloromethanein the presence of triethylamine at room temperature. The product wasused in the next step without purification.

Compound 11_(j) : R_(f) (cis)=0.52 R_(f) (trans)=0.49 (AcOEt)

Compound 11_(k) : R_(f) (rac)=0.60 (AcOEt)

IR (cm⁻¹): ν_(SO2) =1360 and 1180 ¹ H NMR (100 MHz, CDCl₃, TMS, δ),principal signals: Trans compound: 4.9 (t, 1H, H₂); 4.2 (m, 3H, H₅ andCH₂ OMs); 2.9 (s, 3H, SO₂ Me). Cis compound: 4.8 (t, 1H, H₂); 4.2 (t,2H, CH₂ OMes); 4 (m, 1H, H_(5')). Specific signals for compound 11_(k) :5.3 (m, 1H, H₂)

2-aryl 5-[N-benzyl δ-amino propyl]tetrahydrofuran--group compounds II

The condensation of the mesylate 11 and the benzylamine was carried outin boiling acetonitrile, according to the process already described (cf.A-1: Process according to scheme 2, step 3). Purification bychromatography on a silica gel column (eluent CHCl₃ /MeOH 95:5 then90:10) gave the compound II (approximative yield 60%).

Compound II_(j) : R_(f) (cis)=0.48 R_(f) (trans)=0.55 (CHCl₃ /MeOH80:20)

Compound II_(k) : R_(f) (rac)=0.51 (CHCl₃ /MeOH 80:20)

C-2) Process for the preparation of compound II wherein R=alkyl orheteroaryl

The successive steps for the preparation of the compounds 8, 9,10, 11and II respectively, may be performed as described above (cf. C-1).

D) Process for the preparation of the starting compound II disubstitutedin the 2,5-positions with n=7

D-1) Process according to reaction scheme 5, for the preparation ofcompound II wherein R=aryl

2-(bromohexyl-oxy)tetrahydropyran 13

This compound was obtained by bromation of2-(hydroxyhexyl-oxy)tetrahydropyran which may be prepared from 1-6hexanediol and dihydropyran.

¹ H NMR (100 MHz, CDCl₃, TMS, δ), principal signals: 4.6 (m, 1H,O--CH--O); 3.7 (m, 2H, 2H.sub.α O); 3.3 (t, 4H, OCH₂ and CH₂ Br);1.9-1.3 (m, 14H, 7CH₂).

2-(3',4',5'-trimethoxyphenyl)-5-[tetrahydropyran-2-oxyhexyl]tetrahydrofuran14

A mixture of Cu(1)I (0.7 mmol) and compound 2b (trans) in 20 ml of dryTHF, was cooled at -40° C., under nitrogen atmosphere. The Grignardreagent prepared from compound 13 in THF was added dropwise. The mixturewas stirred at this temperature for 30 minutes, raised to roomtemperature then refluxed for 6 hours. After usual work up, the productwas chromatographed (eluent AcOEt) to yield the compound 14_(l) trans(60%). R_(f) (trans)=0.51 (AcOEt)

¹ H NMR (100 MHz, CDCl₃, TMS, δ), principal signals: 6.8 (s, 2H, O); 5(m, 2H, H₂); 4.6 (m, 1H, O--CHO); 4.2 (m, 1H, H₅); 3.9 (d, 9H, 3CH₃ O);3.3 (t, 2H, CH₂ O); 2.6-1.7 (m, 16H, 2H₃, 2H₄, 6CH₂).

The following successive steps for the preparation of compounds 15 andII, may be performed as described above (cf. reaction scheme 4).

D-2) Process for the preparation of compound II wherein R=alkyl orheteroaryl

The successive steps for the preparation of the compounds 12, 13, 14, 15and II respectively, may be performed as described above (cf. D-1).

E) Process for the preparation of the starting compound II disubstitutedin the 2,4-positions with n=1

E-1) Process according to reaction scheme 6, for the preparationcompound II wherein R=aryl

Ethyl 4-aryl-4-oxo-2-cyano-butyrate--group compounds 16

To a suspension of sodium hydride (1.1 equivalents) in anhydrous THF,5.8 g (52 mmol) of ethyl cyanoacetate, in 100 ml of THF, was addeddropwise. The mixture was stirred 30 minutes more then cooled to 0° C.and a solution of 52 mmol of bromomethyl-aryl-ketone in 150 ml of THFwas added slowly. The mixture was allowed to warm to room temperaturethen refluxed for 1 hour. A hydrolysis followed by an extraction withchloroform lead, after the usual workup, to a product. A purification bysilica gel column chromatography (eluent PE/AcOEt 60:40) affordedcompound 16.

Compound 16_(m) : R_(f) =0.5 (PE/AcOEt 50:50)

Compound 16_(n) : R_(f) =0.62 (PE/AcOEt 50:50)

IR (cm⁻¹): ν_(CN) =2240; ν_(CO2Et) =1730; ν_(CO) =1680. ¹ H-NMR (100MHz, CDCl₃, TMS, δ), main signals: 4.3 (q, 2H, OCH₂ CH₃); 4.1 (t, 1H,CH); 3.6 (m, 2H, COCH₂); 1.3 (t, 3H, CH₃).

4-aryl-2-cyano-1,4-dihydroxy-butane--group compounds 17

Compound 17 was obtained by reducing the ketone and ester moieties ofthe compound 16, with LiBH₄ (2.2 equivalents) in THF at roomtemperature. After the usual treatments, a purification on a silica gelcolumn (eluent AcOEt/PE 80:20 then 90:10 then AcOEt) provided the diol17 (yield 75%).

Compound 17_(m) : R_(f) (rac)=0.31 (AcOEt)

Compound 17_(n) : R_(f) (rac)=0.39 (AcOEt)

IR (cm⁻¹): ν_(OH) =3400; ν_(CN) =2240 ¹ H NMR (100 MHz, CDCl₃, TMS, δ),main signals: 5.35 (t, 2H, CHOH); 3.8 (m, 2H, CH₂ OH); 3.15 (m, 1H,CHCN); 2.7 (2H, 2OH exchangeable with D₂ O); 1.9 (m, 2H, CH₂ CHCN)

4-aryl-2-cyano-tetrahydrofuran--group compounds 18

A mixture of diol 17 (28 mmol) and 0.2 g of p-toluene-sulphonic acid in100 ml of anhydrous benzene was refluxed in an apparatus fitted with aDean and Stark trap, for 5 hours. After elimination of the solvent, theresidue was purified by flash chromatography (eluent PE/AcOEt 60:0) toafford compound 18 as cis, trans isomers (yield 75-78%).

Compound 18_(m) : R_(f) (cis)=0.36 R_(f) (trans)=0.41 (PE/AcOEt 50:50)

Compound 18_(n) : R_(f) (cis)=0.46 R_(f) (trans)=0.58 (PE/AcOEt 50:50)

IR (cm⁻¹) ν_(CN) =2240; ν_(C-O-C) =1010 ¹ H NMR (100 MHz, CDCl₃, TMS, δ)Trans compound: 5 (t, 1H, H₂); 4.4 and 4.1 (2m, 2H, 2H₅); 3.3 (m, 1H,H₄); 2.6 and 2.2 (2m, 2H, H₃) Cis compound: 4.8 (t, 1H, H₂); 4.3 and 4.1(2m, 2H, 2H₅); 2.7 and 2.1 (2m, 2H, H₃).

4-aryl-2-aminomethyl-tetrahydrofuran--group compounds 19

The reduction of the nitrile 18 with LiAlH₄ lead to the amine 19 (yield89%).

Compound 19_(m) : R_(f) (rac)=0.49 (CHCl₃ /MeOH/NH₃, 80:19:1)

Compound 19_(n) : R_(f) (rac)=0.51 (CHCl₃ /MeOH/NH₃, 80:19:1)

IR (cm⁻¹) ν_(NH2) =3400 and 3350 ¹ H NMR (100 MHz, CDCl₃, TMS, δ)(mixture): 4.85 (m, 1H, H₂); 4.3-3.6 (m, 4H, 2H₅, CH₂ N); 2.7 (m, 1H,H₄); 2.4 and 2 (2m, 2H, H₃); 1.5 (2H, NH₂ exchangeable with D₂ O).

4-aryl-2-(N-benzyl-aminomethyl)-tetrahydrofuran--group compound II

The amine 19 was condensed with benzoyl chloride and the thus obtainedamide was reduced with LiAlH₄. The product II thus obtained was purifiedon a silica gel column (eluent CHCl₃ /MeOH 98:2 then 95:5).

Compound II_(m) : R_(f) (rac)=0.38 (CHCl₃ /MeOH 98:2)

Compound II_(n) : R_(f) (rac)=0.40 (CHCl₃ /MeOH 98:2)

IR (cm⁻¹): ν_(NH) =3300 ¹ H NMR (100 MHz, CDCl₃, TMS, δ): 7.3 (m, 5H,O); 4.8 (m, 1H, H₂); 4.3-3.5 (m, 6H, 2H₅, CH₂ NCH₂); 2.6 (1H, NH); 2.5-2(2m, 2H, H₃).

E-2) Process for the preparation of compound II wherein R=alkyl orheteroaryl

The successive steps for the preparation of the compounds 16, 17, 18, 19and II respectively, may be performed as described above (cf. E-1).

The following Examples illustrate the invention.

Example 1

2-phenyl-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 and R=phenyl

Step 1

2-phenyl-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyltetrahydrofuranIV

A solution of methyl-5-bromoacetyl salicylate III (1.05 equivalents) in100 ml of anhydrous acetonitrile was added dropwise to a solution of theappropriate amine II (28 mmol) and triethylamine (1.1 equivalents) in120 ml of acetonitrile. The mixture was stirred at room temperature 2.5hours more, then concentrated to dryness and taken up in chloroform.After the usual workup, the residue was purified by flash chromatography(PE/AcOEt 90:10 to 70:30) to yield compound IV (71%). M=473 g

TLC: R_(f) (rac)=0.47 (PE/AcOEt 60:40) IR (cm⁻¹): ν_(OH) =3100;ν_(CO2Me) =1690; ν_(CO) =1670 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ),characteristics signals: Trans compound: 11.2 (1H, OH); 8.5 (d, 1H, H₂);8.1 (2d, 1H, H₆); 7.3 (m, 5H, O); 6.9 (d, 1H, H_(5')); 4.8 (t, 1H, H₂);4.4 (m, 1H, H₅); 3.85 (m, 7H, CO₂ Me, NCH₂ CO, NCH₂ O); 2.8 (d, 2H, CH₂N). Cis compound: 4.2 (m, 1H, H₅); 2.9 (d, 2H, CH₂ N).

Step 2

2-phenyl-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-ethyl]-aminomethyl]-tetrahydrofuranV

To a suspension of LiAlH₄ (3 equivalents) in 50 ml of anhydroustetrahydrofuran (THF), cooled to 0° C. under nitrogen atmosphere, wasadded dropwise a solution of the compound IV as obtained above (16 mmol)in 100 ml of THF. The mixture was allowed to warm to room temperatureand stirred 1.5 hours more. The reaction was quenched in basic medium.After extraction with chloroform and usual workup, the residue waspurified by chromatography (AcOEt/PE 80:20 then AcOEt) to yield V (77%).M=447 g

TLC: R_(f) (rac)=0.24 (CH₂ Cl₂ /MeOH 95:5) ¹ H-NMR (100 MHz, CDCl₃, TMS,δ), characteristics signals: Trans compound: 11.1 (1H, OH); 4.9 (t, 1H,H₂); 4.5 (m, 3H, H₅ and CH₂ OH); 2.8-2.7 (m, 4H, CH₂ NCH₂). Ciscompound: 4.8-4.5 (m, 4H, H₂, H₅ and CH₂ OH).

Step 3

2-phenyl-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]aminomethyl]-tetrahydrofuranI

The compound I was obtained by hydrogenolysis of the compound V asobtained above, in methanol, in the presence of Pd/C 10%, under apressure of 2.7 bar for 2-4 hours. The catalyst was filtered off and thesolvent eliminated. The product was purified by chromatography on asilica gel column (eluent CHCl₃ /MeOH 95:5 then 90:10) to yield compoundI (73%). Purity was checked by thin layer chromatography (TLC) and HPLC.M=343 g

TLC: R_(f) (rac)=0.16 (CHCl₃ /MeOH 80:20). HPLC: reverse phase columnC₁₈ -5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm: T_(R) min=12.5(eluent MeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1 ml/min) IR (cm⁻¹), generalabsorption bands: ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1590; ν_(C) OH=1220; ν_(C-O-C) =1040 ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by heating, under reflux for 5 minutes,an equimolar mixture of the compound I as obtained above and fumaricacid in absolute ethanol. Melting point (°C.): mp (rac)=98

Example 2

2-(3',4',5'-trimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 andR=3,4,5-trimethoxyphenyl

Step 1

2-(3',4',5'-trimethoxyphenyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyltetrahydrofuran IV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate starting compoundII (71%).

M=549 g TLC: R_(f) (cis)=0.42 R_(f) (trans)=0.38 (PE/AcOEt 60:40) IR(cm⁻¹): ν_(OH) =3100; ν_(CO2Me) =1690; ν_(CO) =1670 ¹ H-NMR (100 MHz,CDCl₃, TMS, δ), characteristics signals: Trans compound: 11.2 (1H, OH);8.5 (d, 1H, H_(2')); 8.1 (2d, 1H, H₆); 7.3 (m, 5H, O); 6.9 (d, 1H,H_(5')); 4.8 (t, 1H, H₂); 4.4 (m, 1H, H₅); 3.85 (m, 7H, CO₂ Me, NCH₂ CO,NCH₂ O); 2.8 (d, 2H, CH₂ N). Cis compound: 4.2 (m, 1H, H₅); 2.9 (d, 2H,CH₂ N).

Step 2

2-(3',4',5'-trimethoxyphenyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(77%).

M=523 g TLC: R_(f) (cis)=0.41 R_(f) (trans)=0.43 (AcOEt) ¹ H-NMR (100MHz, CDCl₃, TMS, δ), characteristics signals: Trans compound: 11.1 (1H,OH); 4.9 (t, 1H, H₂); 4.5 (m, 3H, H₅ and CH₂ OH); 2.8-2.7 (m, 4H, CH₂NCH₂). Cis compound: 4.8-4.5 (m, 4H, H₂, H₅ and CH₂ OH).

Step 3

2-(3',4',5'-trimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained above(71%).

M=433 g TLC: R_(f) (cis)=0.25 R_(f) (trans)=0.21 (CHCl₃ /MeOH 80:20)HPLC: reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386;150×4.6 mm: T_(R) min (cis)=12.4; T_(R) min (trans)=7.2 (eluent MeOH/H₂O/TFA 50:50:0.5%--Flow rate 0.5 ml/min) IR (cm⁻¹), general absorptionbands: ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1590; ν_(C) OH =1220;ν_(C-O-C) =1040; ν_(OCH3) =1130 ¹ H-NMR: δ (ppm) (cf table 1) Compound Itrans(+) [α]_(D) ²³ =+32.147 (CHCl₃, 0.871 g/100 ml) Compound I trans(-)[α]_(D) ²³ =-34.2 (CHCl₃, 0.92 g/100 ml)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting points (°C.): mp (cis)=111-113 mp (trans)=124

Example 3

2-(2',3',4'-trimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 andR=2,3,4-trimethoxyphenyl

Step 1

2-(2',3',4'-trimethoxyphenyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyl-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate starting compoundII (76%).

M=549 g TLC: R_(f) (rac)=0.25 (PE/AcOEt 70:30) IR (cm⁻¹): ν_(OH) =3100;ν_(CO2Me) =1690; ν_(CO) =1670 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ),characteristics signals: Trans compound: 11.2 (1H, OH); 8.5 (d, 1H,H_(2')); 8.1 (2d, 1H, H₆); 7.3 (m, 5H, O); 6.9 (d, 1H, H_(5')); 4.8 (t,1H, H₂); 4.4 (m, 1H, H₅); 3.85 (m, 7H, CO₂ Me, NCH₂ CO, NCH₂ O); 2.8 (d,2H, CH₂ N). Cis compound: 4.2 (m, 1H, H₅); 2.9 (d, 2H, CH₂ N).

Step 2

2-(2',3',4'-trimethoxyphenyl)-5-[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(80%).

M=523 g TLC: R_(f) (rac)=0.40 (CH₂ Cl₂ /MeOH 10:90) ¹ H-NMR (100 MHz,CDCl₃, TMS, δ), characteristics signals: Trans compound: 11.1 (1H, OH);4.9 (t, 1H, H₂); 4.5 (m, 3H, H₅ and CH₂ OH); 2.8-2.7 (m, 4H, CH₂ NCH₂).Cis compound: 4.8-4.5 (m, 4H, H₂, H₅ and CH₂ OH).

Step 3

2-(2',3',4'-trimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained above.The cis and trans isomers are separated by preparative HPLC (70%). M=433g

TLC: R_(f) (cis)=0.37 R_(f) (trans)=0.32 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm:T_(R) min (cis)=47; T_(R) min (trans)=45 (eluent MeOH/H₂ O/TFA25:75:0.5%--Flow rate 1 ml/min) IR (cm⁻¹), general absorption bands:ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1590; ν_(COH) =1220; ν_(C-O-C)=1040; ν_(OCH3) =1130 ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (trans)=145

Example 4

2-(2'-chlorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 and R=2-chlorophenyl

Step 1

2-(2'-chlorophenyl)-5-[N-benzyl-N-*3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyl-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate starting compoundII (69%).

M=493.5 g TLC: R_(f) (cis)=0.26 R_(f) (trans)=0.21 (PE/AcOEt 80:20) IR(cm⁻¹): ν_(OH) =3100; ν_(CO2Me) =1690; ν_(CO) =1670 ¹ H-NMR (100 MHz,CDCl₃, TMS, δ), characteristics signals: Trans compound: 11.2 (1H, OH);8.5 (d, 1H, H_(2')); 8.1 (2d, 1H, H₆); 7.3 (m, 5H, O); 6.9 (d, 1H,H_(5')); 4.8 (t, 1H, H₂); 4.4 (m, 1H, H₅); 3.85 (m, 7H, CO₂ Me, NCH₂ CO,NCH₂ O); 2.8 (d, 2H, CH₂ N). Cis compound: 4.2 (m, 1H, H₅); 2.9 (d, 2H,CH₂ N).

Step 2

2-(2'-chlorophenyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxyphenyl)ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(75%).

M=467.5 g TLC: R_(f) (cis)=0.41 R_(f) (trans)=0.44 (PE/AcOEt 10:90) ¹H-NMR (100 MHz, CDCl₃, TMS, δ), characteristics signals: Trans compound:11.1 (1H, OH); 4.9 (t, 1H, H₂); 4.5 (m, 3H, H₅ and CH₂ OH); 2.8-2.7 (m,4H, CH₂ NCH₂). Cis compound: 4.8-4.5 (m, 4H, H₂, H₅ and CH₂ OH).

Step 3

2-(2'-chlorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxyethyl]-aminomethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained abovein presence of PtO₂ instead of Pt/C (73%). M=377.5 g

TLC: R_(f) (cis)=0.18 R_(f) (trans)=0.15 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm:T_(R) min (cis)=38; T_(R) min (trans)=35 (eluent MeOH/H₂ O/TFA25:75:0.5%--Flow rate 1 ml/min) IR (cm⁻¹), general absorption bands:ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1590; ν_(C) OH =1220; ν_(C-O-C)=1040 ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (cis)=90 mp (trans)=80

Example 5

2-(3'-chlorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 and R=3-chlorophenyl

Step 1

2-(3'-chlorophenyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyl-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate starting compoundII (79%).

M=493.5 g TLC: R_(f) (cis)=0.23 R_(f) (trans)=0.29 (PE/AcOEt 80:20) IR(cm⁻¹): ν_(OH) =3100; ν_(CO2Me) =1690; ν_(CO) =1670 ¹ H-NMR (100 MHz,CDCl₃, TMS, δ), characteristics signals: Trans compound: 11.2 (1H, OH);8.5 (d, 1H, H_(2')); 8.1 (2d, 1H, H₆); 7.3 (m, 5H, O); 6.9 (d, 1H,H_(5')); 4.8 (t, 1H, H₂); 4.4 (m, 1H, H₅); 3.85 (m, 7H, CO₂ Me, NCH₂ CO,NCH₂ O); 2.8 (d, 2H, CH₂ N). Cis compound: 4.2 (m, 1H, H₅); 2.9 (d, 2H,CH₂ N).

Step 2

2-(3'-chlorophenyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxyphenyl)-ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtainedabove. M=467.5 g

TLC: R_(f) (cis)=0.35 R_(f) (trans)=0.33 (PE/AcOEt 20:80) ¹ H-NMR (100MHz, CDCl₃, TMS, δ), characteristics signals: Trans compound: 11.1 (1H,OH); 4.9 (t, 1H, H₂); 4.5 (m, 3H, H₅ and CH₂ OH); 2.8-2.7 (m, 4H, CH₂NCH₂). Cis compound: 4.8-4.5 (m, 4H, H₂, H₅ and CH₂ OH).

Step 3

2-(3'-chlorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxyethyl]-aminomethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained abovein presence of PtO₂ instead of Pd/C (73%). M=377.5 g

TLC: R_(f) (cis)=0.17 R_(f) (trans)=0.14 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm:T_(R) min (cis)=35; T_(R) min (trans)=32.5 (eluent MeOH/H₂ O/TFA25:75:0.5%--Flow rate 1 ml/min) IR (cm⁻¹), general absorption bands:ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1590; ν_(C) OH =1220; ν_(C-O-C)=1040 ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (cis)=72 mp (trans)=84

Example 6

2-(2'-fluorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 and R=2-fluorophenyl.

Step 1

2-(2'-fluorophenyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyl]-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate starting compoundII (78%).

M=477.5 g TLC: R_(f) (rac)=0.34 (PE/AcOEt 80:20) IR (cm⁻¹): ν_(OH)=3100; ν_(CO2Me) =1690; ν_(CO) =1670 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ),characteristics signals: Trans compound: 11.2 (1H, OH); 8.5 (d, 1H,H_(2')); 8.1 (2d, 1H, H₆); 7.3 (m, 5H, O); 6.9 (d, 1H, H_(5')); 4.8 (t,1H, H₂); 4.4 (m, 1H, H₅); 3.85 (m, 7H, CO₂ Me, NCH₂ CO, NCH₂ O); 2.8 (d,2H, CH₂ N). Cis compound: 4.2 (m, 1H, H₅); 2.9 (d, 2H, CH₂ N).

Step 2

2-(2'-fluorophenyl)-5-[[N-benzyl-N-β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)ethyl-aminomethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(78%).

M=451 g TLC: R_(f) (rac)=0.46 (PE/AcOEt 10:90) ¹ H-NMR (100 MHz, CDCl₃,TMS, δ), characteristics signals: Trans compound: 11.1 (1H, OH); 4.9 (t,1H, H₂); 4.5 (m, 3H, H₅ and CH₂ OH); 2.8-2.7 (m, 4H, CH₂ NCH₂). Ciscompound: 4.8-4.5 (m, 4H, H₂, H₅ and CH₂ OH).

Step 3

2-(2'-fluorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained abovein presence of PtO₂ instead of Pd/C (75%). M=361 g

TLC: R_(f) (rac)=0.16 (CHCl₃ /MeOH 80:20) HPLC: reverse phase column C₁₈-5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm: T_(R) min (rac)=16.5(eluent MeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1 ml/min) IR (cm⁻¹), generalabsorption bands: ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1,590; ν_(C) OH=1220; ν_(C-O-C) =1040; ν_(C-F) =1230 ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (rac)=170

Example 7

2-(3'-methoxy-4'-propyloxy-5'-methylsulfonyl-phenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 andR=3-methoxy-4-propyloxy-5-methylsulfonyl phenyl.

Step 1

2-(3'-methoxy-4'-propyloxy-5'-methylsulfonyl-phenyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyl-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate starting compoundII (74%).

M=625 g TLC: R_(f) (rac)=0.33 (CH₂ Cl₂) IR (cm⁻¹): ν_(OH) =3100;ν_(CO2Me) =1690; ν_(CO) =1670 ¹ H-NMR (100 MHz, CDCl₃, TMS, δ),characteristics signals: Trans compound: 11.2 (1H, OH); 8.5 (d, 1H,H_(2')); 8.1 (2d, 1H, H₆); 7.3 (m, 5H, O); 6.9 (d, 1H, H_(5')); 4.8 (t,1H, H₂); 4.4 (m, 1H, H₅); 3.85 (m, 7H, CO₂ Me, NCH₂ CO, NCH₂ O); 2.8 (d,2H, CH₂ N). Cis compound: 4.2 (m, 1H, H₅); 2.9 (d, 2H, CH₂ N).

Step 2

2-(3'-methoxy-4'-propyloxy-5'-methylsulfonyl-phenyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(76%).

M=599 g TLC: R_(f) (rac)=0.37 (CH₂ Cl₂ /MeOH 95:5) ¹ H-NMR (100 MHz,CDCl₃, TMS, δ), characteristics signals: Trans compound: 11.1 (1H, OH);4.9 (t, 1H, H₂); 4.5 (m, 3H, H₅ and CH₂ OH); 2.8-2.7 (m, 4H, CH₂ NCH₂).Cis compound: 4.8-4.5 (m, 4H, H₂, H₅ and CH₂ OH).

Step 3

2-(3'-methoxy-4'-propyloxy-5'-methylsulfonylphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained above(75%). The cis and trans isomers are separated by preparative HPLC.M=509 g

TLC: R_(f) (cis)=0.23 R_(f) (trans)=0.19 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm:T_(R) min (cis)=23; T_(R) min (trans)=19 (eluent H₂ O/MeOH/TFA60:40:0.5%--Flow rate 0.6 ml/min) IR (cm⁻¹), general absorption bands:ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1590; ν_(C) OH =1220; ν_(C-O-C)=1040; ν_(SO2Me) =1305; ν_(OCH3) =1140 ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (cis) =156 mp (trans)=126

Example 8

2-(3',4'-dimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxyethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2.5-disubstitution in which n=1 andR=3,4-dimethoxyphenyl.

The steps 1 to 3 were performed as described above (cf. example 1, steps1 to 3) to obtain the required compound. M=403 g

TLC: R_(f) (cis)=0.27; R_(f) (trans)=0.22 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm:T_(R) min (cis)=13.6; T_(R) min (trans)=6.5 (eluent MeOH/H₂ O/TFA50:50:0.5%--Flow rate 0.5 ml/min) ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point(°C.): mp(cis)=118 mp (trans)=129

Example 9

2-(4'-methoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 andR=4-methoxyphenyl.

The steps 1 to 3 were performed as described above (cf. example 1, steps1 to 3) to obtain the required compound. M=373 g

TLC: R_(f) (cis)=0.22; R_(f) (trans)=0.19 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm:T_(R) min (cis)=45; T_(R) min (trans)=41 (eluent MeOH/H₂ O/TFA25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm) (cf table 1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (cis)=101 mp (trans)=112

Example 10

2-(2',6'-dichlorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 andR=2,6-dichlorophenyl.

The steps 1 to 3 were performed as described above (cf. example 4, steps1 to 3) to obtain the required compound. M=412 g

TLC: R_(f) (rac)=0.19 (CHCl₃ /MeOH 80:20) HPLC: reverse phase column C₁₈-5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm: T_(R) min=39 (eluentMeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm) (cf table1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (rac)=92

Example 11

2-propyl-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 and R=propyl.

The steps 1 to 3 were performed as described above (cf. example 1, steps1 to 3) to obtain the required compound. M=309 g

TLC: R_(f) (rac)=0.12 (CHCl₃ /MeOH 80:20) HPLC: reverse phase column C₁₈-5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm: T_(R) min=8.3 (eluentMeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm) (cf table1)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (rac)=127

Example 12

2-(4∝-pyridyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=1 and R=4'-pyridyl.

Step 1

2-(4'-pyridyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyl-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the corresponding startingcompound II (69%).

M=474 g. TLC: R_(f) (rac)=0.25 (CHCl₃ /MeOH 90:10).

Step 2

2-(4'-pyridyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the corresponding compound IV(78%).

M=448 g TLC: R_(f) (rac)=0.20 (CHCl₃ /MeOH 80:20)

Step 3

2-(4'-pyridyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the corresponding compound V inpresence of PtO₂ instead of Pd/C (72%). M=344 g

TLC: R_(f) (rac)=0.18 (CHCl₃ /MeOH 60:40) HPLC: reverse phase column C₁₈-5μ, Nucleosil 125, CFCC 3F 10386; 150×4.6 mm: T_(R) min (rac)=12(eluent MeOH/H₂ O/TFA 15:85:0.5%--Flow rate 0.6 ml/min) IR (cm⁻¹),general absorption bands: ν_(OH) and ν_(NH) =3400-3300; ν_(O) =1590;ν_(C-OH) =1220; ν_(C-O-C) =1040; ν_(pyridine) =1600 and 1560 ¹ H-NMR: δ(ppm) (cf table 1)

Example 13

2-phenyl-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminoethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=2 and R=phenyl

Step 1

2-phenyl-5-[[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminoethyl-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate compound II(73%).

TLC: R_(f) (cis)=0.47 R_(f) (trans)=0.43 (PE/AcOEt 60:40) IR (cm⁻¹):ν_(CO2Me) =1690; ν_(CO) =1675 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principalsignals: Trans compound: 11.2 (1H, OH); 8.5 (d, 1H, H_(2')); 8.1 (2d,1H, H_(6')); 7.3 (s, 5H, OCH₂); 4.9 (t, 1H, H₂); 4.2 (m, 1H, H₅); 4.1(s, 5H, NCH₂ CO and CO₂ Me); 3.8 (2H, NCH₂ O); 2.7 (t, 2H, CH₂ N);2.4-1.5 (m, 8H, H₃, H₄, 2CH₂ of the chain) Cis compound: 4.8 (t, 1H,H₂).

Step 2

2-phenyl-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)ethyl]-aminoethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(70%).

M=445 g TLC: R_(f) (cis)=0.24 R_(f) (trans)=0.28 (CHCl₃ /MeOH 95:5) IR(cm⁻¹): ν_(OH) =3400 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principal signals:Trans compound: 4.9 (t, 1H, H₂); 4.7 (s, 2H, CH₂ OH); 4.6 (m, 1H, H₅);4.15 (m, 1H, CHOH); 3.9 and 3.5 (2d, 2H, NCH₂ O) Cis compound: 4.7 (m,4H, H₅, H₂ and CH₂ OH).

Step 3

2-phenyl-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminoethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained above(71%). M=355 g

TLC: R_(f) (cis)=0.48 R_(f) (trans)=0.40 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386, 150×4.6 mm:T_(R) min(cis)=52; T_(R) min(trans)=48 (eluent: MeOH/H₂ O/TFA25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm) (cf. table 2)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (cis)=145 mp (trans)=130

Example 14

2-(3',4',5'-trimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)[-β-hydroxy-ethyl]-aminoethyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=2 andR=3,4,5-trimethoxyphenyl

Step 1

2-(3',4',5'-trimethoxyphenyl)-5-[[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminoethyl-tetrahydrofuranIV

The compound IV was obtained according to the process as described above(cf. example 1, step 1), starting from the appropriate compound II.

TLC: R_(f) (cis)=0.40 R_(f) (trans)=0.28 (PE/AcOEt 50:50) IR (cm⁻¹):ν_(CO2Me) =1690; ν_(CO) =1675 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principalsignals: Trans compound: 11.2 (1H, OH); 8.5 (d, 1H, H_(2')); 8.1 (2d,1H, H_(6')); 7.3 (s, 5H, OCH₂); 4.9 (t, 1H, H₂); 4.2 (m, 1H, H₅); 4.1(s, 5H, NCH₂ CO and CO₂ Me); 3.8 (2H, NCH₂ O); 2.7 (t, 2H, CH₂ N);2.4-1.5 (m, 8H, H₃, H₄, 2CH₂ of the chain) Cis compound: 4.8 (t, 1H,H₂).

Step 2

2-(3',4',5'-trimethoxyphenyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)ethyl]-aminoethyl]-tetrahydrofuranV

The compound V was obtained according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(72%).

M=535 g TLC: R_(f) (cis)=0.60 R_(f) (trans)=0.65 (CHCl₃ /MeOH 80:20) IR(cm⁻¹): ν_(OH) =3400 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principal signals:Trans compound: 4.9 (t, 1H, H₂); 4.7 (s, 2H, CH₂ OH); 4.6 (m, 1H, H₅);4.15 (m, 1H, CHOH); 3.9 and 3.5 (2d, 2H, NCH₂ O) Cis compound: 4.7 (m,4H, H₅, H₂ and CH₂ OH)

Step 3

2-(3',4',5'-trimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminoethyl]-tetrahydrofuranI

The compound I was obtained according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained above(74%). M=455 g

TLC: R_(f) (cis)=0.18 R_(f) (trans)=0.13 (CHCl₃ /MeOH 80:20) HPLC:reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386, 150×4.6 mm:T_(R) min(cis)=24; T_(R) min(trans)=19.5 (eluent: MeOH/H₂ O/TFA25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm) (cf. table 2)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (cis)=180 mp (trans)=220

Example 15

2-(3',4',5'-trimethoxyphenyl)-5-[-N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminopropyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=3 andR=3,4,5-trimethoxyphenyl

Step 1

2-(3',4',5'-trimethoxyphenyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)-aminopropyl]-tetrahydrofuranIV

The compound IV was prepared according to the process as described above(cf. example 1, step 1), starting from the appropriate compound II(75%). TLC: R_(f) (cis)=0.38 R_(f) (trans)=0.26 (PE/AcOEt 50:50) IR(cm⁻¹): ν_(CO2Me) =1690; ν_(CO) =1675 ¹ H NMR (100 MHz, CDCl₃, TMS, δ)principal signals: Trans compound: 11.2 (1H, OH); 8.5 (d, 1H, H_(2'));8.1 (2d, 1H, H_(6')); 7.3 (s, 5H, OCH₂); 4.9 (t, 1H, H₂); 4.2 (m, 1H,H₅); 4.1 (s, 5H, NCH₂ CO and CO₂ Me); 3.8 (2H, NCH₂ O); 2.7 (t, 2H, CH₂N); 2.4-1.5 (m, 8H, H₃, H₄, 2CH₂ of the chain) Cis compound: 4.8 (t, 1H,H₂).

Step 2

2-(3',4',5'-trimethoxyphenyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)ethyl]-aminopropyl]-tetrahydrofuranV

The compound V was prepared according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(78%).

M=547 g TLC: R_(f) (cis)=0.36 R_(f) (trans)=0.38 (CHCl₃ /MeOH 90:10) IR(cm⁻¹): ν_(OH) =3400 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principal signals:Trans compound: 4.9 (t, 1H, H₂); 4.7 (s, 2H, CH₂ OH); 4.6 (m, 1H, H₅);4.15 (m, 1H, CHOH); 3.9 and 3.5 (2d, 2H, NCH₂ O) Cis compound: 4.7 (m,4H, H₅, H₂ and CH₂ OH).

Step 3

2-(3',4',5'-trimethoxyphenyl)-5-[-N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminopropyl]-tetrahydrofuranI

The compound I was prepared according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained above(72%).

M=457 g TLC: R_(f) (cis)=0.18 R_(f) (trans)=0.15 (CHCl₃ /MeOH 80:20)HPLC: reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386,150×4.6 mm: T_(R) min(cis)=38; T_(R) min(trans)=30 (eluent: MeOH/H₂O/TFA 25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm) (cf. table 3)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (cis)=205 mp (trans)=162

Example 16

2-(2'-chlorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminopropyl]-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=3 and R=2-chlorophenyl

Step 1

2-(2'-chlorophenyl)-5-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)aminopropyl]-tetrahydrofuranIV

The compound IV was prepared according to the process as described above(cf. example 1, step 1), starting from the appropriate compound II(75%).

TLC: R_(f) (rac)=0.40 (PE/AcOEt 70:30) IR (cm⁻¹): ν_(CO2Me) =1690;ν_(CO) =1675 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principal signals: Transcompound: 11.2 (1H, OH); 8.5 (d, 1H, H_(2')); 8.1 (2d, 1H, H_(6')); 7.3(s, 5H, OCH₂); 4.9 (t, 1H, H₂); 4.2 (m, 1H, H₅); 4.1 (s, 5H, NCH₂ CO andCO₂ Me); 3.8 (2H, NCH_(2O)); 2.7 (t, 2H, CH₂ N); 2.4-1.5 (m, 8H, H₃, H₄,2CH₂ of the chain) Cis compound: 4.8 (t, 1H, H₂).

Step 2

2-(2'-chlorophenyl)-5-[[N-benzyl-N-[β-hydroxy-β-(3'-hydroxymethyl-4'-hydroxyphenyl)ethyl]-aminopropyl]-tetrahydrofuranV

The compound V was prepared according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(79%).

M=491.5 g TLC: R_(f) (rac)=0.42 (CHCl₃ /MeOH 95:5) IR (cm⁻¹): ν_(OH)=3400 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) principal signals: Transcompound: 4.9 (t, 1H, H₂); 4.7 (s, 2H, CH₂ OH); 4.6 (m, 1H, H₅); 4.15(m, 1H, CHOH); 3.9 and 3.5 (2d, 2H, NCH₂ O) Cis compound: 4.7 (m, 4H,H₅, H₂ and CH₂ OH).

Step 3

2-(2'-chlorophenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminopropyl]-tetrahydrofuranI

The compound I was prepared according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained above,in presence of PtO₂ instead of Pd/C (73%). M=401.5 g

TLC: R_(f) (rac)=0.14 (CHCl₃ /MeOH 80:20) HPLC: reverse phase column C₁₈-5μ, Nucleosil 125, CFCC 3F 10386, 150×4.6 mm: T_(R) min(rac)=19.4(eluent: MeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm)(cf. table 3)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (rac)=210

Example 17

2-(3',4',5'-trimethoxyphenyl)-5-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminoheptyl-tetrahydrofuran

Compound I, with a 2,5-disubstitution in which n=7 andR=3,4,5-trimethoxyphenyl.

The steps 1 to 3 were performed as described above (cf. example 1, steps1 to 3) to obtain the required compound. M=513 g

TLC: R_(f) (trans)=0.19 (CHCl₃ /MeOH 80:20) HPLC: reverse phase columnC₁₈ -5μ, Nucleosil 125, CFCC 3F 10386, 150×4.6 mm: T_(R) min(trans)=35(eluent MeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1 ml/min) ¹ H-NMR: δ (ppm)(cf. table 4)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. Melting point (°C.): mp (trans)=156

Example 18

2-(3',4',5'-trimethoxyphenyl)-4-[N-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,4-disubstitution in which n=1 andR=3,4,5-trimethoxyphenyl

Step 1

2-(3',4',5'-trimethoxyphenyl)4[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)-aminomethyl]-tetrahydrofuranIV

The compound IV was prepared according to the process as described above(cf. example 1, step 1), starting from the appropriate amine II (yield69%).

TLC: R_(f) (rac)=0.42 (PE/AcOEt 50:50) IR (cm⁻¹): ν_(CO) (ester andketone)=1690 ¹ H NMR (100 MHz, CDCl₃, TMS, δ) characteristics signals:4.7 (m, 1H, H₂); 4.2-3.5 (m, 16H, 4CH₃ O, NCH₂ CO, NCH₂ O); 2.7-1.7 (m,5H, 2H₃, 1H₄ and CH₂ N).

Step 2

2-(3',4',5'-trimethoxyphenyl)-4-[-N-benzyl-N-[β-(3'-hydroxymethyl-4'-hydroxyphenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was prepared according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(yield 70%).

TLC: R_(f) (rac)=0.27 (CHCl₃ /MeOH 85:15) IR (cm⁻¹): ν_(OH) =3450-3300 ¹H NMR (100 MHz, CDCl₃, TMS, δ), characteristics signals: 11 (phenolicOH); 7.3-6.8 (m, 8H, O and H₉, H₁₀, H₁₁); 6.5 (d, 2H, O); 4.8 (m, 3H,OH, H₂ and H₁₂); 3.8 (m, 14H, 3CH₃ O, 2H₅, NCH₂ O and H₈); 2.6-1.9 (m,8H, 3OH, H₆, H₇ and H₄).

Step 3

2-(3',4',5'-trimethoxyphenyl)-4-[N-β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranI

After hydrogenolysis of the compound V, the compound I thus obtained waspurified by chromatography on a silica column (eluent CHCl₃ /MeOH 95:5,90:10 then 70:30) (74%). M=433 g

TLC: R_(f) (rac)=0.23 (CHCl₃ /MeOH 80:20) ¹ H-NMR: δ (ppm) (cf. table 5)HPLC: reverse phase column C₁₈ -5μ, Nucleosil 125, CFCC 3F 10386,150×4.6 mm: T_(R) min=7.5 (eluent MeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1ml/min).

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. M=549 g; Melting point (°C.): 118

Example 19

2-(2'-chlorophenyl)-4-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuran

Compound I, with a 2,4-disubstitution in which n=1 and R=2-chlorophenyl

Step 1

2-(2'-chlorophenyl)-4-[N-benzyl-N-(3'-methoxycarbonyl-4'-hydroxy-phenacyl)]-aminomethyl]-tetrahydrofuranIV

The compound IV was prepared according to the process as described above(cf. example 1, step 1), starting from the appropriate compound II(yield 67%).

TLC: R_(f) (rac)=0.46 (PE/AcOEt 50:50) IR (cm⁻¹): ν_(CO) (ester andketone)=1690 ¹ H NMR (100 MHz, CDCl₃, TMS, δ)characteristics signals:4.7 (m, 1H, H₂); 4.2-3.5 (m, 7H, CH₃ O, NCH₂ CO, NCH₂ O); 2.7-1.7 (m,5H, 2H₃, 1H₄ and CH₂ N).

Step 2

2-(2'-chlorophenyl)-4-[-N-benzyl-N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-β-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranV

The compound V was prepared according to the process as described above(cf. example 1, step 2), starting from the compound IV as obtained above(yield 71%).

TLC: R_(f) (rac)=0.29 (CHCl₃ /MeOH 85:15) IR (cm⁻¹): ν_(OH) =3450-3300 ¹H-NMR (100 MHz, CDCl₃, TMS, δ) characteristics signals: 11 (phenolicOH); 7.3-6.8 (m, 8H, O and H₉, H₁₀, H₁₁); 4.8 (m, 3H, OH, H₂ and H₁₂);3.8 (m, 5H, 2H₅, NCH₂ O and H₈); 2.6-1.9 (m, 8H, 3OH, H₆, H₇ and H₄).

Step 3

2-(2'-chlorophenyl)-4-[N-[β-(3'-hydroxymethyl-4'-hydroxy-phenyl)-.beta.-hydroxy-ethyl]-aminomethyl]-tetrahydrofuranI

The compound I was prepared according to the process as described above(cf. example 1, step 3), starting from the compound V as obtained abovein presence of PtO₂ instead of Pd/C.

TLC: R_(f) (rac)=0.19 (CHCl₃ /MeOH 80:20) HPLC: reverse phase column C₁₈-5μ, Nucleosil 125, CFCC 3F 10386, 150×4.6 mm: T_(R) min=38 (eluentMeOH/H₂ O/TFA 25:75:0.5%--Flow rate 1 ml/min). ¹ H-NMR: δ (ppm) (cf.table 5)

The fumarate salt was prepared by using the compound I as obtained aboveand fumaric acid. M=493.5 g; Melting point (°C.): 79

Table 1

¹ H-NMR (100 MHz, CD₃ OD, TMS, δ): the exchangeable protons are notvisible. δ (ppm) according to the following formula: ##STR7##

Example 1

Racemic: 7.3 (s, 5H); 7.1-6.6 (m, 3H, H₉, H₁₀, H₁₁); 4.9 (m, 1H, H₂);4.6 (s, 2H, H₁₂); 4.4 (m, 2H, H₅ and H₈); 2.8 (m, 4H, H₆ and H₇);2.3-1.7 (m, 4H, H₃ and H₄)

Example 2

Trans: 7.4-6.9 (m, 3H, H₉, H₁₀, H₁₁); 6.8 (s, 2H, O); 5.2 (m, 3H, H₂ andH₁₂); 4.7 (m, 2H, H₅ and H₈); 3.9 (d, 9H, 3CH₃ O); 3.15 (m, 4H, H₆ andH₇); 2.5-1.9 (m, 4H, H₃ and H₄) Cis: 5 (m, 3H, H₂ and H₁₂); 4.5 (m, 1H,H₅)

Example 3

Trans: 7.2-6.9 (2m, 5H, H₉, H₁₀, H₁₁ and O); 5.3 (m, 1H, H₂); 5.1 (s,2H, H₁₂); 4.9 (m, 1H, H₅); 4.7 (m, 1H, H₈); 3.9 (d, 9H, 3CH₃ O); 3.15(m, 4H, H₆ and H₇); 2.5-1.9 (m, 4H, H₃ and H₄) Cis: 4.5 (m, 1H, H₅)

Example 4

Trans: 7.6-7.3 (m, 6H, H₉, H₁₁ and O); 6.9 (d, 1H, H₁₀); 5.5 (t, 1H,H₂); 4.9 (m, 3H, H₁₂ and H₈); 4.7 (m, 1H, H₅); 3.2 (m, 4H, H₆ and H₇);2.6-1.9 (m, 4H, H₃ and H₄) Cis: 5.4 (t, 1H, H₂); 4.5 (m, 1H, H₅); 3.3(m, 4H, H₆ and H₇)

Example 5

Trans: 7.6-7.3 (m, 6H, H₉, H₁₁ and O); 6.9 (d, 1H, H₁₀); 5.3 (t, 1H,H₂); 4.8 (m, 4H, H₁₂, H₈ and H₅); 3.1 (m, 4H, H₆ and H₇); 2.6-1.7 (m,4H, H₃ and H₄) Cis: 4.4 (m, 1H, H₅); 3.3 (m, 4H, H₆ and H₇)

Example 6

Racemic: 7.5-7 (m, 6H, H₉, H₁₁ and O); 6.9 (d, 1H, H₁₀); 5.4 (m, 1H,H₂); 4.7 (m, 3H, H₈ and H₁₂); 4.6 (m, 1H, H₅); 3.1 (m, 4H, H₆ and H₇);2.6-1.7 (m, 4H, H₃ and H₄)

Example 7

Trans: 7.6-7 (m, 4H, H₉, H₁₁ and O); 6.9 (d, 1H, H₁₀); 4.9 (m, 1H, H₂);4.7 (m, 3H, H₁₂ and H₈); 4.5 (m, 1H, H₅); 4 (t, 2H, OCH₂); 3.8 (s, 3H,OCH₃); 3.2 (1, 3H, SO₂ CH₃); 3 (m, 4H, H₆ and H₇); 2.6-1.6 (m, 6H, CH₂,H₃ and H₄); 0.9 (t, 3H, CH₃) Cis: 4.7 (m, 1H, H₂); 4.3 (m, 1H, H₅); 3.2(m, 7H, SO₂ CH₃, H₆ and H₇)

Example 8

Trans: 7.4-7 (m, 3H, H₉, H₁₀, H₁₁); 6.8 (m, 3H, O); 5.2 (m, 3H, H₂ andH₁₂); 4.7 (m, 2H, H₅ and H₈); 3.8 (s, 6H, 2CH₃ O); 3.2 (m, 4H, H₆ andH₈); 2.5-1.9 (m, 4H, H₃ and H₄) Cis: 5 (m, 3H, H₂ and H₁₂); 4.5 (m, 1H,H₅)

Example 9

Trans: 7.4-7 (m, 5H, H₉, H₁₀, H₁₁, O); 6.8 (d, 2H, H in α of OMe); 5.2(m, 3H, H₂ and H₁₂); 4.7 (m, 2H, H₅ and H₈); 3.8 (s, 3H, OCH₃); 3.15 (m,4H, H₆ and H₇); 2.15-1.9 (m, 4H, H₃ and H₄) Cis: 5 (m, 3H, H₂ and H₁₂);4.5 (m, 1H, H₅)

Example 10

Racemic: 7.5-6.9 (m, 6H, H₉, H₁₀, H₁₁, O); 5.5 (t, 1H, H₂); 4.9 (m, 3H,H₁₂ and H₈); 4.6 (m, 1H, H₅); 3.2 (m, 4H, H₆ and H₇); 2.6-1.9 (m, 4H, H₃and H₄)

Example 11

Racemic: 7-6.6 (m, 3H, H₉, H₁₀, H₁₁); 5 (s, 2H, H₁₂); 4.8 (m, 1H, H₈);4.1-3.9 (m, 2H, H₂ and H₅); 3.2 (m, 4H, H₆ and H₇); 2.3-1.4 (m, 8H,4CH₂); 0.9 (t, 3H, CH₃)

Example 12

Racemic: 8.5 (m, 2H, 2H.sub.α N); 7.4-6.9 (m, 5H, 2H pyridine, H₉, H₁₀,H₁₁); 5 (m, 1H, H₂); 4.8-4.5 (m, 4H, H₅, H₈ and 2H₁₂); 3.1 (m, 4H, H₆and H₇); 2.6-1.9 (m, 4H, H₃ and H₄)

Table 2

¹ H-NMR (100 MHz, CD₃ OD, TMS, δ), characteristics signals: δ (ppm)according to the following formula: ##STR8##

Example 13

Trans: 7.3 (s, 5H); 7.1-6.6 (m, 3H, H₁₀, H₁₁, H₁₂); 5.1 (s, 2H, H₁₃); 5(m, 2H, H₂ and H₉); 4.1 (m, 1H, H₅); 3.2 (m, 2H, H₈); 2.75 (m, 2H, H₇);2-1.4 (m, 6H, H₃, H₄ and H₆) Cis: 4.9 (m, 2H, H₂ and H₉); 3.9 (m, 1H,H₅)

Example 14

Trans: 7.4-6.9 (m, 3H, H₁₀, H₁₁, H₁₂); 6.8 (s, 2H, O); 5.2 (s, 2H, H₁₃);5 (m, 1H, H₂); 4.8 (m, 1H, H₉); 4.6 (m, 1H, H₅); 3.9 (d, 9H, 3CH₃ O);3.2 (m, 2H, H₅); 2.5 (m, 2H, H₇); 2.2-1.7 (m, 6H, H₃, H₄, H₆) Cis: 4.8(m, 1H, H₈); 4.3 (m, 1H, H₅)

Table 3

¹ H-NMR (100 MHz, CD₃ OD, TMS, δ), characteristics signals: δ (ppm)according to the following formula: ##STR9##

Example 15

Trans: 7.5-6.9 (m, 3H, H₁₁, H₁₂, H₁₃); 6.7 (s, 2H, O); 5.1 (m, 2H, H₂and H₁₀); 4.9 (s, 2H, H₁₄); 4.3 (m, 1H, H₅); 3.9 (d, 9H, 3CH₃ O); 3.2(m, 4H, H₈ and H₉); 2.6-1.7 (m, 8H, H₆, H₇, H₃ and H₄) Cis: 5 (m, 4H,H₂, H₁₀ and H₁₄); 4.1 (m, 1H, H₅)

Example 16

Racemic: 7.7-6.8 (m, 7H, H₁₁, H₁₂, H₁₃ and O); 5.4 (m, 1H, H₂); 5.1 (s,2H, H₁₄); 4.9 (m, 1H, H₁₀); 4.3 (m, 1H, H₅); 3.2 (m, 4H, H₈ and H₉);2.2-1.3 (m, 8H, H₆, H₇, H₃ and H₄)

Table 4

¹ H-NMR (100 MHz, CD₃ OD, TMS, δ), characteristics signals: δ (ppm)according to the following formula: ##STR10##

Example 17

Trans: 7.4-6.9 (m, 3H, H₁₀, H₁₁, H₁₂); 6.7 (s, 2H, O); 5.1 (m, 2H, H₂and H₉); 4.3 (m, 1H, H₅); 3.9 (d, 9H, 3CH₃ O); 3.2 (m, 4H, t17 and H₅);2.6-1.7 (m, 16H, H₃, H₄ and 6CH₂)

Table 5

¹ H NMR (100 MHz, CD₃ OD, TMS, δ) characteristics signals: δ (ppm)according to the following formula: ##STR11##

Example 18

7.5-6.8 (m, 3H, H₉, H₁₀, H₁₁); 6.7 (d, 2H, O); 4.8 (m, 3H, H₂ and H₁₂);4.3 (m, 1H, H₅); 3.8 (m, 11H, 3CH₃ O and 2H₅); 2.8 (m, 4H, H₆ and H₇);2.3 (m, 3H, H₃ and H₄)

Example 19

7.5-6.8 (m, 6H, H₉, H₁₁ and O); 6.9 (d, 1H, H₁₀); 5 (m, 3H, H₂ and H₁₂);4.4 (m, 1H, H₈); 3.8 (m, 2H, 2H₅); 2.8 (m, 4H, H₆ and H₇); 2.3 (m, 3H,2H₃ and H₄)

Toxicology

No toxicity was noticed for any of the compounds according to theinvention when administered per se, at doses up to 50 mg/kg, to rats andmice. By the IP route, no death was noticed at 30 mg/kg for the sameanimals.

Pharmacology

Compounds of the invention are potent β₂ adrenoceptor agonists with along duration of action on airways smooth muscles and act asbronchodilatators in vivo.

In vitro, radioligand binding studies in lung membrane indicated thatseveral of them have a better affinity for β adrenoceptors thanSalbutamol, used as a reference. The results are summarised in Table A.Generally, the activity is better for the trans than the cis isomer.

In vivo

The different compounds showed a bronchodilatator effect with a durationof action better than Salbutamol in its ability to inhibit acetylcholineinduced bronchoconstriction.

Method

Male Hartley Guinea Pigs (450-500 g) were anaesthetised with ethylcarbamate and prepared for recording bronchoconstriction according toKonzett and Rossler method (Naunym Schmiedebergers Arch. Exp. Path.Pharmakol (1940) 195, 71). To abolish spontaneous respiration, aninjection IV of vecuronium bromide (2 mg/kg) was made.Bronchoconstriction was induced by IV injection of Acetylcholine and theanimals received one dose of β agonist compound (IV) 5 minutes later.Results are given with Salbutamol as reference and are summarised inTable B.

Moreover, the example 2 (cis) showed an α-antagonist activity (bindingα, receptor Ki=61 nM) and was an inhibitor of isolated aorta contractioninduced by phenylephrine (pA₂ : 7.75).

Compounds of the invention compared to Salbutamol, are not more activebut their actions lost a longer time which is a very importantadvantage.

Presentation-Posology

In human therapy, a daily dose is of from 0.01 to 50 mg; for oraladministration, the pharmaceutical composition may take the form of, forinstance, tablets or capsules; by this route, the suitable doses are0.01 mg to 50 mg. By IP route, the corresponding daily doses are 0.01 mgto 20 mg.

                  TABLE A                                                         ______________________________________                                                      BINDING AFFINITY                                                              (Ki, nM)                                                        ______________________________________                                        Salbutamol      2500                                                          Example 1       410                                                           Example 2 (trans)                                                                              80                                                           Example 2 (cis) 410                                                           Example 2 (trans) (+)                                                                          50                                                           Example 2 (trans) (-)                                                                         350                                                           Example 3 (trans)                                                                             1600                                                          Example 4 (trans)                                                                             400                                                           Example 4 (cis) 347                                                           Example 5 (trans)                                                                             750                                                           Example 5 (cis) 760                                                           Example 6       1800                                                          Example 8 (trans)                                                                             1050                                                          Example 8 (cis) 1100                                                          Example 9 (trans)                                                                             590                                                           Example 9 (cis) 810                                                           Example 11      520                                                           Example 12      350                                                           Example 14 (cis)                                                                              1900                                                          Example 15 (trans)                                                                            760                                                           Example 15 (cis)                                                                              1900                                                          Example 16      570                                                           Example 18      1600                                                          ______________________________________                                    

                                      TABLE B                                     __________________________________________________________________________                     BRONCHOCONSTRICTION PROTECTION                                         DOSE   DURATION OF                                                                            SCORE                                               COMPOUNDS μmol/kg, IV                                                                       ACTION (mn)                                                                            5 mn 15 mn                                                                              30 mn                                     __________________________________________________________________________    Salbutamol                                                                              0.13   10       +++  0    0                                                   0.42   30       +++  +++  0                                         Example 1 4.8    0        0    0    0                                         Example 2 (trans)                                                                       0.13   30       +++  ++   +                                                   0.42   >50      +++  +++  +++                                       Example 2 (cis)                                                                         4.6    5        +    0    0                                         Example 3 (trans)                                                                       1.53   5        +    0    0                                                   3.6    30       ++   +    +                                         Example 4 (trans)                                                                       0.46   10       +++  0    0                                                   1.48   >25      +++  ++   ++                                        Example 4 (cis)                                                                         0.46   10       ++   0    0                                                   1.5    <40      ++   ++   +                                         Example 5 (trans)                                                                       0.46   >20      ++   +    +                                         Example 5 (cis)                                                                         0.47   <10      +    0    0                                         Example 6 0.47   <30      ++   +    +                                         Example 8 (trans)                                                                       0.13   30       ++   +    +                                                   0.46   >30      ++   ++   +                                         Example 8 (cis)                                                                         0.48   <30      ++   +    0                                         Example 9 (trans)                                                                       0.46   >30      +++  ++   +                                         Example 9 (cis)                                                                         0.46   20       ++   +    0                                         Example 12                                                                              0.13   >30      ++   +    +                                                   0.42   >30      ++   ++   +                                         Example 14 (cis)                                                                        1.50   30       +++  +    +                                         Example 15 (trans)                                                                      0.42   20       +++  ++   0                                                   4.18   >50      +++  +++  ++                                        Example 16                                                                              1.6    >15      +    +    0                                         Example 18                                                                              1.6    30       ++   +    +                                         __________________________________________________________________________     The score legends are as follows:                                             Score 0: inhibition <20%                                                      Score +: inhibition = 20-50%                                                  Score ++: inhibition = 50-75%                                                 Score +++: inhibition >75%.                                              

We claim:
 1. An N-(2,5-disubstituted tetrahydrofurylalkyl)-N-(phenylethyl-β-ol)amine derivative, of racemic or enantiomerform, of general formula I ##STR12## wherein R represents a straight orbranched alkyl group comprising from 1 to 10 carbon atoms; a heteroarylgroup, a phenyl radical or a substituted phenyl radical of the formula##STR13## in which the radicals R₁, R₂, R₃, R₄ and R₅ independentlyrepresent a hydrogen atom, a halogen atom, an alkoxy radical comprisingfrom 1 to 5 carbon atoms, or an alkylsulphonyl radical comprising from 1to 5 carbon atoms;n is from 1 to 10;and pharmaceutically acceptablesalts thereof.
 2. Pharmaceutical composition comprising a derivativeaccording to claim 1, or a pharmaceutically acceptable salt of such aderivative, in admixture with a pharmaceutically acceptable diluent orcarrier.
 3. An N-(2,4-disubstituted tetrahydrofurylalkyl)-N-(phenylethyl-β-ol)amine derivative, of racemic or enantiomerform, of general formula I ##STR14## wherein R represents a straight orbranched alkyl group comprising from 1 to 10 carbon atoms; a heteroarylgroup, a phenyl radical or a substituted phenyl radical of the formula##STR15## in which the radicals R₁, R₂, R₃, R₄ and R₅ independentlyrepresent a hydrogen atom, a halogen atom, an alkoxy radical comprisingfrom 1 to 5 carbon atoms, or an alkylsulphonyl radical comprising from 1to 5 carbon atoms;n is 1;and pharmaceutically acceptable salts thereof.4. Pharmaceutical composition comprising a derivative according to claim3, or a pharmaceutically acceptable salt of such a derivative, inadmixture with a pharmaceutically acceptable diluent or carrier.
 5. AnN-(2,4-disubstituted tetrahydrofuryl alkyl)-N-(phenylethyl-β-ol)aminederivative, of racemic or enantiomer form, of general formula I##STR16## wherein R represents a straight or branched alkyl groupcomprising from 1 to 10 carbon atoms; a phenyl radical or a substitutedphenyl radical of the formula ##STR17## in which the radicals R₁, R₂,R₃, R₄ and R₅ independently represent a hydrogen atom, a halogen atom,an alkoxy radical comprising from 1 to 5 carbon atoms, or analkylsulphonyl radical comprising from 1 to 5 carbon atoms;n is 1 to10;and pharmaceutically acceptable salts thereof.
 6. Pharmaceuticalcomposition comprising a derivative according to claim 5 or apharmaceutically acceptable salt of such a derivative, in admixture witha pharmaceutically acceptable diluent or carrier.